Rate Of Infusion-related Reactions Research Articles

Comparing the Risk of Infusion-Related Reactions and Tolerability in Patients Given Cetirizine or Diphenhydramine Prior to Ocrelizumab Infusion (PRECEPT).

Background: Ocrelizumab is an effective medication for multiple sclerosis. However, infusion-related reactions (IRRs) are a concern for patients and may lead to discontinuation of ocrelizumab. To minimize IRRs, pre-medications are administered. However, from our experience, these medications, especially diphenhydramine, can cause marked drowsiness. The primary objective of this study was to evaluate whether cetirizine is non-inferior to diphenhydramine in limiting the proportion and severity of reactions from ocrelizumab infusions. Methods: Twenty participants were serially randomized in a 1:1 ratio to receive 10 mg of cetirizine or 25 mg of diphenhydramine orally prior to their first three ocrelizumab infusions. Results: The rate of IRRs in this study was similar across both treatment groups with no increase in the risk of severity, and no grade 3 IRRs. Further, patients receiving cetirizine experienced a reduction in fatigue. While there was not a significant difference in global satisfaction, this score increased over time in the cetirizine arm while it remained unchanged in the diphenhydramine arm. Conclusions: Overall, our results suggest that cetirizine does not increase the risk of infusion-related reactions compared to diphenhydramine.

Evaluation of cost and infusion-related reactions among intravenous trastuzumab, subcutaneous trastuzumab, and trastuzumab biosimilars at an academic medical center.

Trastuzumab is a vital treatment option for human epidermal growth factor 2 positive breast cancer. Since 2017, there have been 5 trastuzumab biosimilars approved for use. Despite hypotheses of infusion-related reactions among intravenous trastuzumab, subcutaneous trastuzumab, and trastuzumab biosimilars, there is minimal available literature comparing these agents. This evaluation will compare the rate of infusion-related reactions among these agents, evaluate our institution's utilization, and compare acquisition costs to determine if there is a potential cost savings by utilizing specific agents as our formulary preferred medication. We retrospectively analyzed medical records to identify the incidence of infusion-related reaction after administration of intravenous or subcutaneous trastuzumab or trastuzumab biosimilars. Additionally, we conducted a cost analysis to identify potential cost savings by switching to an alternative institutional preferred agent. Infusion chair time was calculated to identify chair time savings with subcutaneous administration. There were 183 patients included in this study. Seven patients (3.8%) experienced an infusion-related reaction. The most utilized agent within our cohort was intravenous trastuzumab. During our study period, 181 patients received intravenous infusions, which could allow for substantial infusion chair savings by switching to trastuzumab/hyaluronidase, the subcutaneous formulation. Beyond the chair time, direct drug cost savings were also identified when comparing the costs of each of the evaluated medications. Subcutaneous trastuzumab or trastuzumab biosimilars do not pose a greater risk of infusion-related reactions compared to intravenous trastuzumab and may offer more affordable treatment options for breast cancer patients who qualify for trastuzumab therapy.

Safety and tolerability study of sotrovimab (VIR-7831) prophylaxis against COVID-19 infection in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity

BackgroundMultiple vaccines have been approved since August 2021 to prevent infection with SARS-CoV-2; however, 20–40% of immunocompromised people fail to develop SARS-CoV-2 spike antibodies after COVID-19 vaccination and remain at high risk of infection and more severe illness than non-immunocompromised hosts. Sotrovimab (VIR-7831) is a monoclonal neutralizing antibody that binds a conserved epitope on the SARS-CoV-2 spike protein. It is neither renally excreted nor metabolized by P450 enzymes and therefore unlikely to interact with concomitant medications (e.g., immunosuppressive medications). In this open-label feasibility study protocol, we will define the optimal dose and dosing interval of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals as well as its safety and tolerability in this population specifically.MethodsWe will enroll 93 eligible immunocompromised adults with a negative or low-positive (< 50 U/mL) SARS-CoV-2 spike antibody. In phase 1, the first 10 patients will participate in a lead-in pharmacokinetics (PK) cohort study to determine the optimal dosing interval. Phase 2 will expand this population to 50 participants to examine rates of infusion-related reactions (IRR) with a 30-min 500 mg sotrovimab IV infusion. Phase 3 will be an expansion cohort for further assessment of the safety and tolerability of sotrovimab. In phase 4, the first 10 patients receiving 2000 mg IV of sotrovimab on the second sotrovimab infusion day will comprise a lead-in safety cohort that will inform the duration of observation following administration of the drug. The patients will be followed for safety and COVID-19 events for 36 weeks after the second dose.DiscussionIn a previous phase III randomized, placebo-controlled pivotal trial, there were no significant differences in the prevalence of adverse events in patients receiving sotrovimab vs. placebo. Thus, we propose an open-label feasibility study protocol of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals to evaluate its PK in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity and define optimal dosing intervals. We also aim to determine COVID-19 infections over the study period and self-reported quality of life measures throughout the study.Trial registrationClinicalTrials.gov Identifier: NCT05210101.

Prevention of amivantamab infusion related reactions with extended pre-infusion day oral steroid therapy.

e21083 Background: Initial results with amivantamab (ami) in CHRYSALIS-1, and ami and lazertinib (laz) regimen in CHRYSALIS-2 showed encouraging efficacy in patients whose disease progressed after standard-of-care chemotherapy, and osimertinib (osi) and platinum-based chemotherapy respectively. Infusion related reactions however were frequent; 65% all grades in both studies and 2%/7% respectively had &gt;Grade 3 infusion related reactions. An on-going trial (NCT05663866) utilising dexamethasone (dex), montelukast and methotrexate to minimise ami infusion related reactions might be unacceptable to many patients; a simpler method would be more ideal. Ami has been available in Singapore since the third quarter of 2021. Laz is not commercially available in South Asia as at Jan 2023. Methods: A single medical oncologist in private practice in Singapore managing advanced lung cancer patients collated this cohort of 7 consecutive patients treated from August 2021 to Jan 2023 with ami. Infusion day pre-medication and infusion protocol were according to the ami product insert. All patients were EGFR mutation positive and treatment-refractory with KPS &lt;2. All who were on EGFR Tyrosine Kinase Inhibitors (TKI) concomitant with ami had tolerated these agents before and upon rechallenge of the TKI. Oral dex 8mg BD for three days (starting two days before ami) was implemented for patients 5-7 after observing patients 3-4 with &gt;Grade 3 infusion related reactions. Fisher exact test evaluated the statistical significance of the difference in the incidence rate of infusion related reactions between the patients who did and did not receive pre-infusion day steroids. Results: 0/5 and 2/2 patients with and without pre-infusion day steroids respectively had infusion related reactions (p = 0.0476). Both reactions were &gt; Grade 3. Patient 4 did not have any infusion related reactions from Doses 2 to 6 once pre-infusion day dex was given. Conclusions: Premedicating with oral dex 8mg BD for 3 days starting 2 days prior to ami was able to prevent all-grades infusion related reactions. This approach should be confirmed in a larger study given the ease of such an intervention to make ami infusion safer. [Table: see text]

Clinical Pharmacokinetics and Pharmacodynamics of Daratumumab.

Daratumumab is a fully human, monoclonal immunoglobulin G1 and a first-in-class CD38-targeting drug approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory and newly diagnosed multiple myeloma or newly diagnosed light-chain amyloidosis. CD38 is heavily expressed on malignant myeloma cells, and daratumumab exerts anti-myeloma activity via immune-mediated mechanisms, direct induction of apoptosis, and immunomodulation. Daratumumab is used as monotherapy or in combination with standard-of-care myeloma therapies, including proteasome inhibitors, immunomodulatory agents, DNA-alkylating agents, and corticosteroids. Following an intravenous infusion, daratumumab exhibits nonlinear pharmacokinetics (PK), as clearance decreases with higher doses and over time because of target-mediated effects. Dosing schedules vary depending on indications and co-administered drugs, but generally daratumumab is administered weekly for 6-9 weeks followed by a less frequent dosing regimen, once every 2-4 weeks. Daratumumab exposure is strongly correlated with efficacy, and the exposure-efficacy relationship follows a maximal effect model, whereas exposure is not correlated with safety endpoints. The approved dose of 16 mg/kg of daratumumab results in the saturation of 99% of the target at the end of weekly dosing in most patients, and high target saturation is maintained over time during the less frequent dosing schedule. Infusion-related reactions are frequently observed in patients given daratumumab, particularly with the first infusion, thus prompting long durations of infusion (~ 7 h) and splitting of the first dose across 2 days. This led to the development of a subcutaneous delivery formulation for daratumumab (Dara-SC). Dara-SC provides a similar efficacy and safety profile to intravenous daratumumab (Dara-IV) but has a much lower rate of infusion-related reactions and a shorter infusion time. Exposure-response relationships for efficacy and safety endpoints were similar between Dara-SC and Dara-IV, and co-administered drugs with either Dara-IV or Dara-SC do not significantly affect daratumumab PK. Except for baseline myeloma type and albumin level, none of the other investigated disease and patient characteristics (renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group performance status) was identified to have clinically relevant effects on exposure to daratumumab monotherapy or combination therapy regimens. Dara-IV exposure was significantly lower in patients with immunoglobulin G myeloma compared with patients with non-immunoglobulin G myeloma (p < 0.0001) and in patients with a lower albumin level, whereas the overall response rate was similar regardless of the myeloma type and albumin level. Daratumumab dose adjustment is not currently recommended based on disease and patient characteristics.

Interchangeability and adverse events in originator-rituximab and its biosimilar (CT-P10) among rheumatic patients: a real-life experience.

Biosimilars offer cost-effective and safe treatment options both for patients and healthcare systems. CT-P10 is the first biosimilar of rituximab approved in Europe for use in all indications of originator rituximab (oRTX). This study aimed to provide real-life data on treatment changes and adverse events in patients who received oRTX or CT-P10. We retrospectively reviewed treatment-related adverse events [infusion-related reactions (IRRs), infections, hypogammaglobulinemia] in patients treated with at least one dose of oRTX (MabThera®) or CT-P10 (Truxima®) between 2020 and 2021 and had at least 6months follow-up after rituximab infusion in a rheumatology clinic. The switches between oRTX and CT-P10 were performed according to drug availability at the hospital pharmacy at the time of infusion according to the local hospital procedure. Physicians were not involved in the decision of biosimilar selection. A total of 128 patients (CT-P10, n = 64; oRTX, n = 64) were included. CT-P10 was switched in 52 (40.6%) patients who had previously used oRTX, and 48 (37.5%) patients remained on oRTX. We demonstrated no difference between patients treated with oRTX or CT-P10 in the rates of IRRs, in which all reactions were grade 1 and 2. Comparable rates of infections (p > 0.05) and the rate of hypogammaglobulinemia (p > 0.05) were found in both groups with no significant difference. CT-P10 provides a safe treatment alternative in patients who require rituximab therapy. The rational use of biosimilars can be supported by evolving evidence on interchangeability and switching in real-life settings, which will help clinicians in decision-making.

PB1995: SAFETY OF SUBCUTANEOUS DARATUMUMAB IN MULTIPLE MYELOMA: A RETROSPECTIVE MULTI-CENTER REAL LIFE EXPERIENCE

Background: Daratumumab, an anti-CD38 monoclonal antibody, is approved for Multiple Myeloma (MM) treatment at an intravenous (IV) dosage of 16 mg/kg with high rates of infusion-related reactions (IRR; 45-56%), especially at the first infusion. However, the subcutaneous (SC) formulation has shown comparable efficacy with lower IRR risk and with shorter administration time (3-5 minutes) compared to IV daratumumab as reported in PAVO (NCT02519452), COLUMBA (NCT03277105) and PLEIADES (NCT03412565) clinical trials. Approved SC daratumumab dosage is 1800 mg, independently from patient variables including renal failure or body weight. Aims: Here, we investigate safety of SC daratumumab in different MM regimens in a multi-center real-life experience Methods: A total of 29 MM patients (Table 1) who received at least one dose of SC daratumumab at 1800 mg in any association regimen since December 2021 was included in this retrospective study. Enrolled patients were daratumumab-naïve starting directly with SC formulation combined with any association regimen displayed in Table 1. Primary end point was SC daratumumab safety, especially for IRR incidence and severity. Results: All patients received premedication with dexamethasone, paracetamol and antihistamine according to current guidelines and montelukast was used in 23 out of 29 (79%) cases. Median number of SC administrations for single patient was 3 (range 1-10), and administration time ranged from 3 to 5 minutes. One patient (3%) experienced grade III IRR in two consecutive administrations, and grade I hematological and grade I gastroenteric toxicities (diarrhea) were observed in 3 (10%; 2 thrombocytopenia and 1 neutropenia) and 1 (3%) cases Image:Summary/Conclusion: In our multicenter retrospective experience, SC daratumumab showed high safety with a very low (3%) IRR rate, even inferior to that reported in PAVO and PLEIADES trials, despite we included in our study patients with renal failure, different body weights or without montelukast premedication. Of note, IV daratumumab induced IRR especially during the first exposition, while we reported a very low IRR rate with SC daratumumab also during first administrations (median number of cycles, 3). The only patient with grade III IRRs weighted 65 kg, did not have renal failure and did not receive montelukast premedication. The patient was switched to IV daratumumab without further IRR suggesting an SC formulation excipient-related intolerance rather than daratumumab-induced reaction. However, IRR incidence was low to analyze hypothetical associations between predisposing factors and IRR insurgence. In conclusions, our real-life findings showed that SC daratumumab is very manageable with an excellent safety profile and very short administration time. Further validation on larger and prospective clinical studies are needed

Subcutaneous daratumumab (DARA SC) versus active monitoring in patients (pts) with high-risk smoldering multiple myeloma (SMM): Randomized, open-label, phase 3 AQUILA study.

TPS8075 Background: Standard of care for SMM includes active monitoring until progression to multiple myeloma (MM); however, recent evidence suggests pts with high-risk features may benefit from early treatment. DARA is a human IgGκ monoclonal antibody targeting CD38 that is approved as monotherapy for relapsed/refractory MM (RRMM) or in combination with standard of care for RRMM or newly diagnosed MM. Results from the phase 3 COLUMBA study showed that DARA SC demonstrated similar efficacy to intravenous (IV) DARA but with a lower rate of infusion-related reactions and shorter administration time. Based on the promising single-agent activity observed with IV DARA in intermediate- or high-risk SMM pts during the phase 2 CENTAURUS study, we hypothesized that DARA SC may delay progression to MM versus active monitoring in pts with high-risk SMM. Methods: AQUILA is an ongoing, randomized, open-label, multicenter phase 3 study of DARA SC versus active monitoring in pts with high-risk SMM. DARA SC (DARA 1,800 mg + recombinant human hyaluronidase PH20 [rHuPH20; 2,000 U/mL; Halozyme]) is administered by manual injection over approximately 5 minutes at alternating locations on the abdomen weekly in Cycles 1 and 2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter until 39 cycles (28 days/cycle), up to 36 months, or until disease progression. Eligibility criteria include confirmed diagnosis of SMM for ≤5 years, factors indicating high risk of progression to MM (clonal bone marrow plasma cells [BMPCs] ≥10% and ≥1 of the following: serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8 to &lt; 100, or clonal BMPCs &gt; 50% to &lt; 60% with measurable disease), and ECOG performance status ≤1. The primary endpoint is progression-free survival (PFS), assessed by an independent review committee, with disease progression defined according to International Myeloma Working Group diagnostic criteria for MM. Secondary endpoints include time to biochemical or diagnostic (SLiM-CRAB) progression, overall response rate, complete response rate, duration of response, time to response, time to first-line treatment for MM, PFS on first-line treatment for MM (PFS2), overall survival, and incidence of MM with adverse prognostic features. The study completed enrollment on May 6, 2019; 390 pts have been randomly assigned to DARA SC or active monitoring. The primary efficacy analysis will be performed after approximately 165 PFS events have been observed. Clinical trial information: NCT03301220.

Final analysis of the phase III non-inferiority COLUMBA study of subcutaneous versus intravenous daratumumab in patients with relapsed or refractory multiple myeloma.

In the primary analysis of the phase III COLUMBA study, daratumumab by subcutaneous administration (DARA SC) demonstrated non-inferiority to intravenous administration (DARA IV) for relapsed or refractory multiple myeloma (RRMM). Here, we report the final analysis of efficacy and safety from COLUMBA after a median of 29.3 months follow-up (additional 21.8 months after the primary analysis). In total, 522 patients were randomized (DARA SC, n=263; DARA IV, n=259). With longer follow-up, DARA SC and DARA IV continued to show consistent efficacy and maximum trough daratumumab concentration as compared with the primary analysis. The overall response rate was 43.7% for DARA SC and 39.8% for DARA IV. The maximum mean (standard deviation [SD]) trough concentration (cycle 3, day 1 pre-dose) of serum DARA was 581 (SD, 315) µg/mL for DARA SC and 496 (SD, 231) µg/mL for DARA IV. Median progression-free survival was 5.6 months for DARA SC and 6.1 months for DARA IV; median overall survival was 28.2 months and 25.6 months, respectively. Grade 3/4 treatment-emergent adverse events occurred in 50.8% of patients in the DARA SC group and 52.7% in the DARA IV group; the most common (≥10%) were thrombocytopenia (DARA SC, 14.2%; DARA IV, 13.6%), anemia (13.8%; 15.1%), and neutropenia (13.1%; 7.8%). The safety profile remained consistent with the primary analysis after longer follow-up. In summary, DARA SC and DARA IV continue to demonstrate similar efficacy and safety, with a low rate of infusion-related reactions (12.7% vs. 34.5%, respectively) and shorter administration time (3-5 minutes vs. 3-7 hours) supporting DARA SC as a preferable therapeutic choice. (Clinicaltrials gov. Identifier: NCT03277105.

‘Fast but not so Furious’: Short observation time after subcutaneous Daratumumab administration is both a safe and cost-effective strategy

BackgroundDaratumumab, an anti-CD38 monoclonal antibody, is a key component in the treatment paradigms of multiple myeloma and AL amyloidosis in both the newly diagnosed and relapsed and/or refractory setting. Intravenous (IV) daratumumab administration requires extended infusion times and is associated with higher rates of infusion related reactions (IRRs) when compared to the subcutaneous (SC) formulation. We report real world safety outcomes and infusion chair time savings associated with SC administration in daratumumab naïve patients. MethodsWe retrospectively analyzed medical records at our institution for the incidence and severity of IRRs following differing observation periods post SC daratumumab administration. Infusion chair time was calculated to quantify chair time savings with SC administration. ResultsSixty-six daratumumab naïve patients were included. Nine percent of patients developed IRRs with SC daratumumab with all reactions occurring within six hours of the first dose. All reactions were grade ≤ 2 in severity and were reversible with supportive care. Over the 18 month study period, a total of 904 SC doses were administered, amounting to a potential 1785 hours of infusion chair time savings when compared to IV administration. ConclusionSC daratumumab may be given safely with a short initial observation period and without observation for subsequent doses, resulting in reduced infusion chair time as well as administration related cost and resources.

The safety and clinical effectiveness of rapid infusion with CT-P10 in patients with non-Hodgkin's lymphoma or chronic lymphocytic leukemia: A retrospective non-interventional post-authorization safety study in Europe.

Rapid infusion (RI) of the rituximab biosimilar CT‐P10 is currently only an approved treatment regimen for the treatment of rheumatoid arthritis. Although both CT‐P10 and reference rituximab are known to be frequently administered using a RI regimen (≤90 min) in clinical practice, published data on the safety of RI of CT‐P10 in patients with NHL and CLL are limited. Hence, this study collected real‐world safety and effectiveness data on RI‐CT‐P10 from the medical records of 196 patients with NHL or CLL in 10 European centers, 6 months after the date of the first RI (index date); the infusion‐related reaction (IRR) rate was compared to previously published data. Ten percent (95% confidence interval 6%–15%; n = 20/196) of patients experienced an infusion‐related reaction (IRR) on day 1–2 post‐index, which was not significantly different (p = 0.45) to the IRR rate for rituximab described in a previous meta‐analysis (8.8%). During the observation period, 2% of patients experienced grade 3–5 IRRs and 85% (n = 166) experienced an adverse event (non‐IRR). The most common reason for discontinuation of first‐line CT‐P10 was planned treatment completion (81%; n = 158). Complete response and partial response to CT‐P10 was observed in 74% (n = 142/192) and 22% (n = 42/192) of patients, respectively. The results of this real‐world study demonstrate that the safety and effectiveness profile of RI‐CT‐P10 is similar to RI of reference rituximab and therefore support the current use of RI‐CT‐P10 in patients with NHL and CLL.

Pre-medication protocols for the prevention of paclitaxel-induced infusion related reactions: a systematic review and meta-analysis.

Prophylaxis against infusion-related reactions (IRR) from paclitaxel with steroids and antihistamines is a standard of care due to high rates of IRR. This systematic review and meta-analysis aimed to comprehensively summarize the evidence behind various prophylaxis strategies. EMBASE, MEDLINE, PubMed, and the Cochrane Register of Controlled Trials were searched (1946 to May 14, 2021). The primary outcomes were Grade 3/4 IRR and any-grade IRR. Secondary outcomes included treatment delay or discontinuation and adverse events secondary to pre-medications. Of the 1285 unique citations, 26 studies were selected: 11 studies for quantitative analysis and 15 studies for qualitative analysis. Studies included randomized controlled trials and observational studies (n = 25-281). There was a non-significant benefit in favour of oral steroids starting 12h prior to paclitaxel administration versus intravenous steroids immediately prior to paclitaxel administration for grade 3/4 IRRs, with a risk difference (RD) of 2% [95%CI 0 to 5%], any-grade IRR with a RD of 4% [95%CI: -1% to 9%] and treatment discontinuation with a RD of 1% [95%CI -1% to 2%]. For de-escalation strategies, a point-estimate for any-grade IRR was 0.44% [95% CI, 0 to 0.02, p = 0.98] and for grade 3/4 IRR was 3.1% (95% CI, 0.02 to 0.07, p = 0.11). Although studies have high risk of bias and risk, differences between steroid routes of administration were small, there was a non-significant trend in favour of oral steroids. De-escalation strategies after two previous successful paclitaxel infusions have an overall low incidence rate of severe IRR and warrant further prospective clinical trials. Insufficient evidence remains to recommend for or against other interventions for the prevention of paclitaxel IRR.

Ibrutinib plus Obinutuzumab as Frontline Therapy for Chronic Lymphocytic Leukemia Is Associated with a Lower Rate of Infusion-Related Reactions and with Sustained Remissions after Ibrutinib Discontinuation: A Single-Arm, Open-Label, Phase 1b/2 Clinical Trial NCT0231576.

Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials (https://Clinicaltrials.gov Identifier https://clinicaltrials.gov/ct2/show/NCT02315768).

The effect of cryopreserved and noncryopreserved stem cells on the outcome of autologous stem-cell transplantation in multiple myeloma patients: A single-center experience

Background The CD34+ stem cells are either noncryopreserved (non-CP) or cryopreserved (CP) in autologous stem-cell transplantation (ASCT). Some retrospective studies have shown that engraftment failure and engraftment rate are similar in CP cells and infusion reactions are lower in CP cells due to the absence of dimethyl sulfoxide. Objective In this study, we presented our clinical experience comparing the outcomes and safety of ASCT with CP and non-CP stem cells. Patients and methods A total of 163 patients were enrolled between January 2019 and June 2021. Duration of neutrophil/platelet engraftment, rates of infusion-related reactions, febrile neutropenia, and duration of hospitalization were compared between the CP and non-CP groups. Results Fifty five (33.7%) received CP cells, 108 (66.3%) received non-CP cells. The median dose of CD34+ cells was similar in both groups (P=0.755). The median duration of neutrophil and platelet engraftment was not statistically significantly different in CP and non-CP groups (P=0.896 and 0.183, respectively). No statistical difference was observed in the median duration of hospitalization between the two groups [CP: 16 (13–26) vs. non-CP: 15 (11–31) days, P=0.124]. The febrile neutropenia rate was higher in the CP group, but there was no statistical difference between the two groups (CP: 56.4% vs. non-CP, 48.1%, P=0.301). The rates of infusion-related reaction such as nausea, vomiting, and rash were higher in the CP group (21.8 vs. 12%), with no statistically significant difference (P=0.159). Conclusion Non-CP cells have similar outcomes to CP cells and lower toxicity than CP cells, which are safe and effective in ASCT.

Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR

Preliminary Results of the Filo Phase 2 Trial for Untreated Fit Patients with Intermediate Risk Chronic Lymphocytic Leukemia Comparing Ibrutinib Plus Venetoclax (IV) Versus FCR

Safety of Emapalumab in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis (HLH): Relationship to Treatment Exposure

▪Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, immune disorder characterized by a hyperinflammatory state in which interferon gamma (IFNγ) is considered a key cytokine. The treatment goal of primary HLH is to stabilize the disease by controlling the associated hyperinflammation to bring patients to allogeneic hematopoietic stem cell transplantation (HSCT), the only curative therapy so far. Current conventional therapy for HLH is based on immunochemotherapies, namely etoposide and glucocorticoids; this treatment, however, is associated with opportunistic infections and severe myelotoxicity. Emapalumab, a fully human, anti-IFNγ monoclonal antibody that neutralizes IFNγ, is the only FDA-approved treatment for primary HLH patients with refractory, recurrent or progressive disease, or intolerance to conventional HLH therapy. In patients with primary HLH, the pharmacokinetics (PK) of emapalumab is highly influenced by body weight, and also by IFNγ production due to target-mediated drug disposition. In the pivotal trial (Locatelli et al NEJM 2020;382:1811-22), treatment of primary HLH patients with emapalumab was associated with a favorable safety and tolerability profile, with no unexpected safety concerns.Objective: To describe prespecified exploratory exposure-safety analyses that were performed on data from patients with primary HLH receiving emapalumab in the pivotal trial.Methods: Data from a multicenter, open-label, pivotal phase 2/3 study (NCT01818492) and its long-term follow-up study (NCT02069899) were included in this analysis. The safety of emapalumab was assessed in 34 patients (27 treatment experienced; 7 treatment naïve) with active primary HLH. Emapalumab was initiated at a dose of 1 mg/kg administered intravenously every 3 days, on a background of dexamethasone 5-10 mg/kg/day. Subsequent doses could be increased to 3, 6 and 10 mg/kg, if required, based on predefined laboratory and clinical response parameters. Treatment duration was up to 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to time of transplantation if needed. Exploratory graphical analyses were performed to determine the incidence of adverse events (AEs) as a function of the exposure parameters at the time of the AE. The relationship between emapalumab exposure and the incidence of treatment-emergent AEs, serious AEs, severe AEs, and AEs related to infections and infusion-related reactions (IRRs) was explored by logistic regression analyses. Selected parameters of renal (creatine clearance [CRCL]) and liver (total bilirubin [TBIL] and alanine aminotransferase [ALT]) function were explored graphically. Exposure parameters were obtained from the population PK/pharmacodynamic (PD) data file that was used for the population PK and PK/PD analyses. Observed individual concentration-time data were used to derive the individual exposure parameters as a function of time. The analyses considered AEs that emerged after the start of the first infusion until last infusion and prior to initiation of HSCT conditioning.Results: Exploratory graphical exposure-safety analyses did not reveal any apparent relationship between the number of AEs and exposure to emapalumab. Logistic exposure-safety regression analyses using the observed exposure to emapalumab at the time of an AE for patients experiencing an event and the highest observed exposure to emapalumab for those patients experiencing no AE, indicated that the incidence of AEs did not increase as a function of increasing emapalumab concentration. In fact, a statistically significant decrease in the incidence of severe AEs and the incidence of AEs related to IRRs was observed. No multivariate effects were identified in the multivariate regression analyses. No clear trend was observed for TBIL, ALT or CRCL as a function of the duration of emapalumab treatment. The exposure of emapalumab did not appear to influence the levels of TBIL, ALT or CRCL in individual patients during treatment.Conclusion: In this study, the exposure-safety evaluation did not reveal any significant relationships between exposure to emapalumab and observed incidence rates of AEs, serious AEs, infections, or IRRs. These findings support the primary evidence of a favorable benefit-risk profile of emapalumab across the dose range used in this fragile patient population. DisclosuresJordan: Sobi: Consultancy. Locatelli: Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Jazz Pharamceutical: Speakers Bureau; Takeda: Speakers Bureau. Jacqmin: Sobi: Consultancy. Laveille: Sobi: Consultancy. Snoeck: Sobi: Consultancy. de Min: Sobi: Consultancy, Ended employment in the past 24 months.

Characteristics of Daratumumab Reactions in Patients Who Transitioned from Intravenous Daratumumab to Subcutaneous Daratumumab

IntroductionDaratumumab based therapy has become standard of care in the treatment of Multiple Myeloma and Systemic Light chain Amyloidosis. The intravenous (IV) infusion of daratumumab is associated with a high rate of infusion-related reactions necessitating use of rescue medications and prolonged chair time. The Phase 3 COLUMBA trial reported non-inferiority of the subcutaneous (SC) daratumumab as compared to IV formulation with significantly reduced rates of daratumumab reactions for new-start patients. However, there is limited data on the characteristics of reactions in patients transitioning between formulations.MethodsThis single center retrospective chart review was performed on consecutive patients who previously received IV daratumumab but subsequently converted to SC daratumumab between June 2020 and June 2021. In this study, severity of allergic reactions and potential predictors of SC daratumumab reaction were assessed.ResultsOf the 45 patients who received SC daratumumab during the study period, a total of 13 patients had previously received IV daratumumab. All patients were premedicated per package insert guidelines and institutional standard of care. Patients were predominately Caucasian (77%), Male (84.6%), and undergoing therapy for Multiple myeloma (69%) and AL Amyloidosis (31%). A mean of 19 doses of IV daratumumab were administered prior to transition to SC formulation. The majority of patients (53.8%) transitioned to SC daratumumab had previously reacted to IV daratumumab. All IV daratumumab reactions occurred during the first infusion. Two patients had experienced Grade 3 reactions to IV daratumumab, requiring inpatient observation to complete the initial infusion but tolerated subsequent doses.Of the 13 patients transitioned to SC daratumumab, two patients (15.4%) experienced daratumumab reactions. Patient 1 had a history of grade 3 IV daratumumab reaction to the first infusion and experienced a Grade 2 reaction at 3 hour 50 minutes with symptoms of cough, shortness of breath, palpitations, itching, and myalgia to the first SC daratumumab dose. Subsequent SC daratumumab doses were tolerated without adverse reactions. The other patient had a history of grade 2 IV daratumumab reaction who noted worsening weakness and diarrhea in the first several days post-injection with the new formulation, and ultimately transitioned back to the IV formulation.ConclusionAlthough SC daratumumab is well tolerated in patients previously treated with IV daratumumab, patients with history of prior first IV daratumumab infusion reactions are still at increased risk of early or delayed daratumumab related reactions with first time exposure to SC daratumumab. DisclosuresGupta: Deva Oncology: Consultancy. Raza: Amgen: Honoraria, Speakers Bureau; drrx, acasti, amicus, abbot: Other: previous stock holder (currently does not hold these stocks); Gilead: Current holder of individual stocks in a privately-held company; Janseen: Honoraria, Speakers Bureau; Takeda: Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite: Honoraria, Membership on an entity's Board of Directors or advisory committees; Moderna , Biontec, Stryker: Current holder of individual stocks in a privately-held company; novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau.

Assessment Of Hypersensitivity Reactions and Feasibility Of a 60 Minute Rapid Infusion Rituximab Protocol At a Comprehensive Cancer Center

IntroductionRituximab (R) is a chimeric monoclonal antibody with approved indications for non-hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Infusion reactions among patients with NHL are common during the first infusion (incidence of 77%), but decrease with subsequent infusions. Consequently, infusions have been gradually titrated, which may take more than three hours for completion depending on dose and tolerability. However, emerging data suggest that rapid infusion protocols may be safe for patients who receive the first dose with minimal infusion toxicity. MethodsThe purpose of this study was to assess the feasibility of a rapid infusion R protocol in a comprehensive cancer center's outpatient infusion center. The primary outcome measure was the incidence of grade 3 and 4 hypersensitivity reactions during a 60 minute infusion protocol of R in patients with B-cell malignancies. Secondary objective included infusion time savings of a 60 minute infusion of R versus a standard titration schedule, as well as nursing satisfaction. Patients were enrolled in this prospective, single institution, single arm study which was approved by the investigational review board. Inclusion criteria included age >18 years, diagnosis of indolent or intermediate grade B-cell malignancy, second R infusion within 3 months of first infusion, and planned outpatient treatment with a regimen including R therapy at a dose of 375mg/m2. Patients were excluded for diagnosis of an aggressive lymphoma histology, absolute lymphocyte count > 10 x 103/µL, enrollment on another clinical trial, allergy to murine-containing medications, exposure to R (<6 months from first dose) prior to enrollment in this study, or grade 3 or 4 hypersensitivity reaction during first R infusion. All patients received the first dose of R by the standard titration schedule as described in the package insert. The investigational protocol was instituted for the second R administration. The infusion began at 100mg/hr administered over 15 minutes and the remaining dose was given over 45 minutes. All patients received 50mg of oral diphenhydramine and 650mg of oral acetaminophen as premedication. To calculate time savings between rapid infusion and standard titration, each patient served as their own control. Nursing data collection included monitoring vitals every 15 minutes (blood pressure, heart rate, temperature, respiratory rate), start and stop times of R infusion, description and grade of hypersensitivity reactions, administration of rescue medications during infusion, and survey assessment of nursing satisfaction. ResultsFrom October 2010 to April 2013, 52 patients were enrolled to the study. Fifty received rapid infusion over 60 minutes during the second R administration. The 2 patients who did not continue on study were deemed ineligible. Patient 1 expired secondary to disease progression after signing consent and patient 2 experienced a grade 3 reaction following end of first infusion. The median age was 63 years (19-85) with 60% female. Chemotherapy regimens included: R-cyclophosphamide, doxorubicin, vincristine, prednisone (RCHOP, n = 19), single-agent R (n = 14), R-bendamustine (BR, n=7), R-cyclophosphamide, vincristine, prednisone (RCVP, n=4), R-gemcitabine, oxaliplatin (RGEMOX, n=3), R-fludarabine, cyclophosphamide (FCR, n=1), R-pentostatin, cyclophosphamide (PCR, n=1) and R-bortezomib (n=1). The rate of infusion related reactions (all grades) observed with the rapid infusion protocol was 0% (1-sided 97.5% CI 0-7.1%). The mean time for the rapid R infusion was 62.4 (95% CI 61.2-63.6) minutes. When compared to the standard second dose infusion recommendations, a mean time of 94.2 (95% 90-98.4) minutes was saved with rapid infusion. Post infusion nursing surveys demonstrated 100% satisfaction with administration of rapid infusion over standard titration practice. ConclusionsA 60 minute rapid rituximab infusion can be safely administered in an outpatient infusion center. The faster infusion allows for less resource utilization and increased nursing satisfaction. Disclosures:No relevant conflicts of interest to declare.

Results of an Interim Safety Analysis of a Phase 2 Study of Daratumumab (Dara) Plus Cyclophosphamide, Bortezomib, and Dexamethasone (CyBorD) in Previously Untreated and Relapsed Patients (Pts) with Multiple Myeloma (MM)

Background: Dara is a monoclonal anti‐CD38 antibody approved for the treatment of relapsed and refractory MM, but is associated with an infusion related reaction (IRR) rate of 46% for infusion 1 and 2% for infusion 2, and a median duration of infusions 1 and 2 of 7.0 and 4.3 hours, respectively (US Prescribing Information). CyBorD is a commonly used bortezomib based regimen for MM. This study was designed to evaluate Dara-CyBorD, as well as administration of the first Dara infusion as a divided dose over 2 days, in pts with MM who are previously untreated or have relapsed following only one line of therapy. We report results from a planned interim analysis of the first 48 pts who completed C1 of study treatment, focusing on the safety and IRR profile of Dara.Methods: This is a multicenter, single-arm, open-label, Phase 2 study conducted at US community oncology centers. Key eligibility criteria include ≥ 18 years of age; documented MM per IMWG 2015 criteria; measurable MM; ECOG performance score of 0, 1, or 2; and no or one prior line of therapy. Approximately 100 pts will receive 4 to 8 28-day induction cycles of Dara-CyBorD, including oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or IV dexamethasone 40 mg weekly. Dara is administered at a dose of 8 mg/kg IV on Days 1 and 2 of C1, then 16 mg/kg IV weekly from C1D8 through C2, then 16 mg/kg IV once every 2 weeks for C3-6, then 16 mg/kg IV once every 4 weeks for cycles 7-8. After completion of induction, pts may undergo an autologous stem cell transplant. All pts then receive 12 cycles of maintenance therapy with Dara 16 mg/kg IV every 4 weeks. Required pre-infusion medications are dexamethasone, acetaminophen, and diphenhydramine; montelukast is allowed at the investigator's discretion.Results: The first 48 pts completed 1 cycle of therapy with no discontinuations during C1. Median age was 62.5 (range 41-80) years, and 65% were male. Thirty-nine pts (81%) were previously untreated, and 9 pts (19%) had received 1 prior therapy. Forty-seven pts (98%) experienced at least 1 treatment emergent adverse event (TEAE) during C1, including 35 pts (73%) who experienced TEAE(s) attributed to Dara by the investigator. No grade 5 AE was reported during C1. The most commonly reported AEs during C1 were nausea (29%), fatigue (25%), diarrhea (23%), headache (17%), and chills (15%). Serious AEs (SAEs) occurred in 10% of pts during C1; no SAE was attributed to Dara by the investigator. IRRs occurred in 44% of pts, all grade ≤ 2, including 38% at C1D1 and 4% at C1D2. The most common IRRs were chills (13%), cough (6%), and nausea (6%). Respiratory IRRs occurred in 13% of pts, including cough (6%), dyspnea (4%), bronchospasm (2%), throat irritation (2%), and oropharyngeal pain (2%). The median infusion time was 4.3 hours for C1D1 and 3.5 hours for C1D2.Conclusion: The overall safety profile during C1 of Dara-CyBorD was consistent with that previously reported for Dara with no new safety concerns. Administration of the first Dara infusion as a split dose of 8 mg/kg/day over 2 days resulted in a similar IRR rate and a shorter median infusion time for C1D1 than the US prescribing information for single dose. No grade ≥ 3 IRRs were observed. These findings demonstrate that splitting of the first Dara infusion in the community setting is feasible, results in a similar IRR rate with no observed grade ≥ 3 IRRs, and reduces the median time for the first Dara infusion. DisclosuresYimer:Bellucum Pharma: Equity Ownership; Juno pharma: Equity Ownership. Melear:Janssen: Membership on an entity's Board of Directors or advisory committees. Faber:Millenium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Bensinger:Janssen: Membership on an entity's Board of Directors or advisory committees. Burke:Incyte: Consultancy; Bayer: Consultancy; Genentech: Consultancy; Celgene: Consultancy, Other: Travel grant; Gilead: Consultancy. Gunawardena:Janssen: Employment. Sean:Janssen: Employment, Equity Ownership. Parros:Janssen: Employment. Lutska:Janssen: Employment. Darif:Janssen: Employment, Equity Ownership. Londhe:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment; Johnson & Johnson, LLC: Equity Ownership. Ukropec:Janssen: Employment. Lin:Janssen: Employment. Rifkin:McKesson Specialty Health: Employment; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2.

8004 Background: D-VTd plus ASCT was approved for transplant-eligible (TE) NDMM based on part 1 of CASSIOPEIA. We report a prespecified interim analysis of CASSIOPEIA part 2: DARA maintenance vs OBS in pts with ≥partial response (PR) in part 1, regardless of induction/consolidation (ind/cons) treatment. Methods: CASSIOPEIA is a 2-part, randomized, open-label, phase 3 study in TE NDMM. Pts received 4 cycles ind and 2 cycles cons with D-VTd or VTd. 886 pts who achieved ≥PR were rerandomized to DARA 16 mg/kg IV Q8W for up to 2 yr (n = 442) or OBS (n = 444) until progressive disease per IMWG. Pts were stratified by ind (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and post cons response ≥PR). Primary endpoint was progression-free survival (PFS) after second randomization. This interim analysis assessed efficacy and safety after 281 PFS events. A preplanned hierarchical procedure tested key secondary endpoints: time to progression (TTP), ≥complete response (CR), MRD negativity rates by NGS and overall survival (OS). Results: At median follow-up of 35.4 mo, median PFS was not reached (NR) with DARA and 46.7 mo with OBS (HR 0.53; 95% CI 0.42–0.68; P &lt;0.0001). PFS advantage for DARA was consistent across most subgroups. However, a prespecified analysis showed significant interaction with ind/cons treatment arm ( P&lt; 0.0001). PFS HR for DARA vs OBS was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. Median TTP was NR for DARA vs 46.7 mo for OBS (HR 0.49; 95% CI 0.38–0.62; P &lt;0.0001). More pts in the DARA vs OBS arm achieved ≥CR (72.9% vs 60.8%; OR 2.17; 95% CI 1.54–3.07; P &lt;0.0001). MRD negativity (in ≥CR pts at 10-5) was 58.6% with DARA vs 47.1% with OBS (OR 1.80; 95% CI 1.33–2.43; P= 0.0001). Median OS was NR in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) with DARA vs OBS were pneumonia (2.5% vs 1.4%), lymphopenia (3.6% vs 1.8%), and hypertension (3.0% vs 1.6%). Serious AEs occurred in 22.7% (DARA) vs 18.9% (OBS) of pts; the most common (≥2.5%) was pneumonia (2.5% vs 1.6%). 13 (3.0%) pts discontinued DARA due to an AE. The rate of infusion-related reactions was 54.5% (DARA-naïve pts) and 2.2% (prior DARA pts); 90% were grade 1/2.Second primary malignancies occurred in 5.5% (DARA) vs 2.7% (OBS) of pts. Conclusions: CASSIOPEIA part 2 demonstrated a clinical benefit of DARA maintenance in TE NDMM pts, with significantly longer PFS for DARA vs OBS. With current follow-up, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons with or without DARA maintenance achieved similar PFS; longer follow-up is needed for PFS2 and OS. DARA significantly increased deeper response and MRD negativity rates vs OBS, and was well tolerated with no new safety signals. Clinical trial information: NCT02541383.